Josephine van Dongen

Chapter 1 8 Introduction In this general introduction, the background and relevance for the Risk-group Infant Vaccination Against Rotavirus (RIVAR) project are described. Based on the characteristics of rotavirus as a pathogen and the induced illness, it follows that vaccination is the only way to prevent disease. Reviewing the existing literature on rotavirus vaccination and its gaps, the aims of this thesis are described. Additionally, the outline of this thesis is presented. Rotavirus disease Rotavirus is the most common cause of acute gastroenteritis (AGE) in children. 1 Before the introduction of vaccination, rotavirus was the dominant cause of severe AGE leading to hospitalization and mor tality. 2 Worldwide it was responsible for 40% of hospital admissions and 450.000 annual deaths among children. 3 In the Netherlands, the incidence rate of hospitaliza- tion due to rotavirus infection was estimated at approximately 500 per 100.000 child years for children below five years of age. 4 Since the introduction of rotavirus vaccinations in national im- munization programs in Europe, pediatric rotavirus hospitalizations in those countries declined with 65 to 84%. 5 In the Netherlands no rotavirus vaccination program has been introduced, uptake of rotavirus vaccine in the private market is estimated to be low (less than one percent). Genetics and viral characteristics Rotaviruses are non-enveloped double-stranded RNA viruses.They have a complex structure of three outer layers surrounding a 11 segmented genome ( Figure 1 ).The genome encodes for six structural proteins (viral protein 1,2,3,4,6,7) and six non-structural proteins (NSP1-6). Based on VP6, that defines the inner membrane of rotavirus, ten groups of rotaviruses can be distin- guished, group A to J. Group A is most common in humans. 6 Fur ther distinction in genotypes is based on outer membrane VP7 (glycoprotein G ) and spike protein VP4 (defining protealysing protein P, see figure 1 ). 6,7 So far 36 different G types and 51 P types are defined. 8 Six of them represent 90% of circulating types of rotavirus among humans; G1P[8], G2P[4], G3P[8], G4P[8], G9P[8] and G12P[8].9 G1P[8] is most common worldwide. 9 The virus is transmitted via the fecal-oral route.The viral density in feces of infected persons is estimated 10 10 viral par ticles per gram stool and only a very limited number of virus par ticles (around 100) are needed to infect a susceptible host. 9,10 Infected surfaces enhance transmission; the virus remains infectious for several hours on hands and up to 60 days on inanimated surfaces. 11,12 Once infected, the virus infects and replicates in the enterocytes and entero-endocrine cells of the small intestines. 9,13 For binding to enterocytes the virus uses glycans on the cell surface.These glycans are par t of the histoblood group antigen-complex (HBGAs). 9,14 The HBGA phenotype of the host defines, in par t, how rotavirus genotypes bind to enterocytes. Diversity in HBGA phenotypes across populations worldwide can explain geographic differences in genotype dominance. 14